Variants in Three Genes Linked with Increased Cervical Cancer Risk

Human papilloma virus, illustration
Human papilloma virus (HPV), computer illustration. HPV causes warts, which mostly occur on the hands and feet. Certain strains also infect the genitals. Although most warts are non-malignant (not cancerous), some strains of HPV have been associated with cancers, especially cervical cancer.

Research led by Imperial College London has revealed three genes—PAX8, CLPTM1L and HLA-DQA1—containing variants that increase a woman’s risk for cervical cancer.

The genome-wide association study, one of the first of its kind for cervical cancer or precancer, was carried out in samples from more than 150,000 women of European descent from the UK Biobank cohort and validated in a second Finnish cohort.

Cervical cancer impacts approximately 570,000 women around the world, with more than 13,000 cases diagnosed in the U.S. each year.  It remains one of the most common female cancers despite extensive screening and vaccination against the human papilloma virus (HPV), which is known to be the main cause of cervical cancer.

“HPV causes cervical cancer, but what we haven’t understood until now is why many people are infected with HPV, yet very few develop cervical cancer,” said Sarah Bowden, M.D., a researcher from the Department of Surgery and Cancer at Imperial College London and lead author on the paper describing the study published in The Lancet Oncology.

“Over 70% of people are infected with HPV over their lifetime, yet most women clear the infection, and only a small fraction go on to develop abnormal pre-cancerous cervical cells; even fewer develop cervical cancer.”

There has long been some uncertainty about the degree to which genetic variants can impact a woman’s risk for developing cervical cancer. Previous studies suggest that the genetic contribution to the risk of cervical cancer ranges from 27-36%, but only seven earlier studies have looked at genetic variants that could contribute to this risk and these have all been fairly modest in size.

This study included 4,769 women with invasive cervical cancer or precancerous neoplasms and 145,545 controls. The women were aged 40-69 years and of European origin.

Out of 9,600,464 SNPs included in the GWAS, six variants were linked with increased risk for cervical cancer or precancerous lesions that could lead to cervical cancer. In a Finnish replication cohort of 128,123 individuals, FinnGen, three of these associations were successfully replicated.

The three significant associations were found with SNPs in the PAX8, CLPTM1L and HLA-DQA1 genes. While gene variants in the HLA region have previously been linked with cervical cancer, the association with the PAX8 and CLPTM1L genes was new.

HLA genes are strongly linked to immune system function, whereas the PAX8 protein triggers hormones important for growth regulation, brain development and metabolism and is expressed in the endometrium and ovaries. CLPTM1L is often overexpressed in lung tumors and the gene lies within a cancer susceptibility region. Inhibition of this protein can help stop tumor formation in some cancers.

The research team also looked at other factors that could predispose women to cervical cancer and confirmed previous links with smoking, age at pregnancy and number of sexual partners.

While more work is needed to investigate the newly discovered genetic links, this study is a step in the right direction to understanding more about cervical cancer and how it could be treated.

“Once genetic testing becomes more widespread, looking at a patient’s genetic information alongside cervical screening could help identify individuals who need close monitoring or treatment,” said Bowden.

“Increased genetic information could also lead to new drugs in the future. At the moment, if a woman is found to have a pre-cancerous cervical abnormality, the options are to ‘watch and wait’, which means regularly check-ups, or a treatment to surgically remove part of the cervix. This can increase the risk of a late miscarriage or preterm birth in future pregnancies. But if we knew more about the interaction between genetics and HPV, we might be able to develop new drugs to treat these abnormalities at an early stage.”

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